The present invention provides for 8-hydroxy-7-substituted quinoline compounds and pharmaceutically acceptable salts thereof which are useful as antiviral agents. The invention also relates to a pharmaceutical composition containing such compound in combination with a suitable excipient, the composition being useful in combating viral infections. The invention also relates to a method for selectively combating viral infections in animals, including man. Specifically, these compounds have anti-viral activity against the herpes virus, cytomegalovirus (CMV). Many of these compounds are also active against other herpes viruses, such as the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus, and the human herpes virus type 8 (HHV-8).
The herpesviruses comprise a large family of double stranded DNA viruses. The herpesvirus family can be divided into three subfamilies (xcex1, xcex2, xcex3) based upon a number of biological properties such as host range and tropism, viral life cycle, and viral persistence and latency. Eight of the herpesviruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and human herpes viruses 6, 7, and 8 (HHV-6, HHV-7, and HHV-8), have been shown to infect humans.
HSV-1 and HSV-2 are the prototypic ot-herpesviruses. These two serotypes share approximately 50% nucleotide homology. Both are neurotropic viruses, but their primary sites of replication are different. HSV-1 typically infects the oral mucosa resulting in ulcerations commonly refered to as cold sores. HSV-2 infects and cuases ulcerations of the genital mucosa. HSV infection can also result in disseminated disease and encephalitis, especially in immunocompromised patients. D. O. White and F. J. Fenner, In Medical Virology, D. O. White and F. J. Fenner, eds., Academic Press, p. 318-347 (1994).
VZV is also an xcex1-herpesvirus and is the causitive agent of chicken pox. VZV establishes a latent infection in the dorsal root ganglia of the peripheral nervous system. From its latent site, VZV can cause recurrent disease commonly refered to as shingles or zoster. The probability of shingles increases with age and frequently occurs in immunocompromised patients. A. M. Arvin, In Virology, B. N. Field, D. M. Knipe, and P. M. Howley, ed., Lippincott-Raven Press, New York, p. 2547-2586 (1996).
Human cytomegalovirus (HCMV), a xcex2-herpesvirus, is an ubiquitous agent producing infection in individuals of all age groups. Infection rates of 60-100%, depending on geographic area and socioeconomic status have been reported. R. J. Whitley, S. Goldsmith and J. Gnann, In Society for General Microbiology. 45th Symposium: Control of Virus Diseases, Mimmock, N. J.; P. D. Griffiths and C. R. Madely, eds., Cambridge University Press, Cambridge, p. 315 (1990). The majority of infections are asymptomatic. However infections occuring in the immuno-compromised patient, including organ transplant recipients and individuals with AIDS may be severe and include HCMV induced pneumonia, colitis, and retinitis. L. W. Drew, Clin. Infect. Dis. 14:608-615 (1992). HCMV is the leading cause of blindness in AIDS patients. T. C. Merigan and S. Resta, Rev. Infect. Dis.12:S693 (1990). HCMV also establishes lifelong latency in the host.
HCMV DNA polymerase (HCMV pol) is an enzyme essential for viral replication. D. H. Spector, K. M. Klucher, D. K. Rabert and D. A. Wright, In Herpesvirus Transcription and Its Regulation, E. K. Wagner, ed., CRC Press, Boca Raton, Fla., p. 261: (1991). The current therapies for HCMV; Ganciclovir, Foscarnet and Vistide act by inhibition of HCMV pol. A. K. Field and K. K. Biron, Clin. Micro. Reviews 7:(1) 1-13 (1994). See also U.S. Pat. Nos. 4,199,574; 4,215,113; 4,355,032; and E. DeClercq et al., Antiviral Research, Vol 8, pages 261-272 (1987). Ganciclovir and Foscarnet display significant toxicity and induction therapy is restricted to an intravenous route of administration. D. Faulds and R. C. Heel, Drugs, 39:597 (1990). Maintenance therapy with Ganciclovir and Foscarnet will likely contribute to drug resistant virus. A. K. Field and K. K. Biron, Clin. Micro. Reviews 7:(1) 1-13 (1994). Clearly less toxic, orally bioavailable alternatives are needed.
EBV is a xcex3-herpesvirus which replicates in the epithelial cells of the nasopharynx and salivary glands and resides latently in xcex2-cells. Childhood infections of EBV are normally asymptomatic. However, EBV infection is associated with several diseases in adults such as infectious mononucleosis, Burkitt""s lymphoma, nasopharyngeal carcinoma, and Hodgkins disease. A. B. Rickinson and E. Kieff, In Virology, B. N. Fields, D. M. Knipe, and P. M. Howley, eds., Lippincott-Raven Press, New York, p. 2397-2446 (1996).
HHV-6 is a xcex2-herpesvirus which causes roseola (exanthem subitum) in children. P. Lusso, Antivir. Res. 31:1-21 (1996). HHV-7 shares 50-60% nucleotide sequence homology with HHV-6. It""s disease association is unclear, but it may be involved in some cases of roseola. N. Frenkel and E. Roffman, In Virology, B. N. Fields, D. M. Knipe, P. M. Howley, eds., Lippincott-Raven Press, New York, p. 2609-2622 (1996). HHV-8, also known as Kaposi""s sarcoma associated herpesvirus (KSHV), is a xcex3-herpesvirus which has recently been associated with Kaposi""s sarcoma in AIDS patients and multiple myeloma. M. B. Rettig et al., Science, 276:1851-1854 (1997).
Published Japanese patent application H1-136152 published May 29, 1989 discloses a silver halide photographic light-sensitive material comprising a support, and thereon, at least 1 silver halide emulsion layer containing a cyan dye-forming coupler represented by a broad generic formula. This broad generic formula includes 8-hydroxy-quinoline derivatives substituted by a wide variety of substituents, e.g., substituted carboxamide groups at the 7-position. None of the specific compounds disclosed in this reference are structurally similar to the compounds of the present invention. Also, the compounds of the present invention are useful as pharmaceutical agents, specifically HCMV inhibitors, whereas the reference compounds are useful in color photography.
Published Japanese patent application HEI 3-73949 published Mar. 29, 1991 discloses a thermally developable color light-sensitive material comprising at least a light-sensitive silver halide, a reducing agent, a binder, and a coupler represented by a first generic formula and/or a second generic formula on a support. These broad generic formulas include 8-hydroxy-quinoline derivatives substituted by a wide variety of substituents, e.g., substituted carboxamide groups at the 7-position. As noted for the previous Japanese reference, none of the specific compounds disclosed in this reference are structurally similar to the compounds of the present invention. Also, the compounds of the present invention are useful as pharmaceutical agents, specifically HCMV inhibitors, whereas the reference compounds are useful in color photography.
Published Japanese patent application 02152966 A2 discloses 4-hydroxy-carbostyryl derivatives as anti-allergy and antuinflammatory agents. The compounds of the present invention are 1-(N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.
U.S. Pat. No. 4,959,363 discloses 1-(N-substituted)-1,4-dihydro-4-oxo-6-and/or-7-substituted-3-quinolinecarboxamides as antiviral agents. The compounds of the present invention are 1-(N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.
U.S. Pat. Nos. 5,459,146 and 5,506,236 disclose 4-substituted-3-alkyl-pyrazolo[3,4-b]quinoline compounds as antiviral agents. Basically, these compounds are the tricyclic version of compounds such as those disclosed in the ""363 patent above, and are structurally very different from the compounds of the present invention.
U.S. Pat. No. 5,378,694 discloses compounds such as 1-(N-substituted)-3-substituted-4-hydroxy-2-quinolinones, and generically, 3-substituted-4-hydroxycoumarin compounds as antiviral agents. U.S. Pat. No. 5,412,104 discloses compounds similar to those disclosed in the ""694 patent for anti-viral or anti-hypertensive use; however, these 1-(N-substituted) reference compounds are disclosed as having substituents other than hydroxy at the 4-position of the quinolinone ring. The compounds of the present invention are 1-(N-unsubstituted)-8-hydroxy-7-quinolinecarboxamides.
German patent DE 1 908 548 discloses a variety of compounds including 4-hydroxy-quinoline compounds which may be substituted at the 3-position by carboxamide groups, and which are useful against cold viruses.
Published German patent application DE 44 25 647 A1 discloses heterocyclic-1-phenyl substituted quinolone and naphthyridone carboxylic acids for treating retroviral infections; Published German patent application DE 44 25 648 A1 discloses 6 and 6,8-substituted 1-[4-(1H-1,2,4-triazol-1-yl-methyl)phenyl]quinolone carboxylic acids for treating retroviral infections; Published German patent application DE 44 25 650 A1 discloses substituted triazolylmethylphenyl- naphthyridone carboxylic acids for treating retroviral infections; Published German patent application DE 44 25 659 A1 discloses N1-diverse 6-fluoro-8-difluoromethoxy substituted quinolone carboxylic acids for treating retroviral infections. The compounds of these references are structurally very different from the compounds of the present invention.
Derwent Abstract 96-246942/25 of JP 8099957-A discloses optionally heterocyclyl substituted 4-oxo-quinoline and naphthyridine derivatives which are useful for treating herpes, particularly herpes simplex virus, herpex zoster virus and cytomegalovirus.
Derwent Abstract 95-271358/36 of JP 7165748-A discloses compounds having heterocyclic ketones which are used in antiviral agents for treating cytomegalovirus infectious disease.
Nowhere do these references teach or suggest the specific 8-hydroxyquinoline-7-carboxamide compounds of the present invention which are useful as anti-HCMV agents.
U.S. Pat. No. 5,463,072 discloses a process for the preparation of naphtholic 2-equivalent cyan couplers which are useful in color photography. It discloses an 8-hydroxy-quinoline compound having a substituted triazole moiety at the 6-position and a carbamoyl moiety at the 7-position.
International Publication WO 95/11592, published May 4, 1995, discloses a marine structure carrying a coating comprising a layer which contains a quinoline compound, or an N-oxide or a salt thereof, having antifouling activity. It generically discloses such compounds with a variety of substituents, such as hydroxy, (optionally substituted C1-12-alkyl)sulphonyl, (optionally substituted aryl)sulphonyl, mono or di (optionally substituted C1-12alkyl)aminosulphonyl.
Derwent Abstract 91-232424/32 (Sandoz AG) discloses the use of 5HT-3 antagonists for the prevention or reduction of dependence on alcohol, psycho-stimulants, nicotine or opiates. A variety of compounds is disclosed including quinoline compounds having unsubstituted phenyl rings.
Derwent Abstract 90-343755/46 (Sandoz Ltd.) discloses serotonin 5-HT3 antagonists used for treating stress-related psychiatric disorders, rhinitis, nasal disorders and lung embolism. It discloses a variety of compounds, including quinoline compounds substituted by bridged piperidine groups.
Derwent Abstract 90-290145/38 (DuPont DeNemours Co.) discloses n-substituted naphthalene or quinoline sulphonamides which are radio and chemo-sensitising agents in tumour treatment. Other than the sulfonamide bonds, the quinoline compounds are not further substituted on their phenyl rings.
Derwent Abstract 90-264471/35 (Yoshitomi Pharm. Ind. KK.) discloses (iso)quinoline-sulphonamide compounds and their acid addition salts as vasodilators and cerebral circulation improving agents.
Derwent Abstract 85-063337/11 (Sandoz-Patent-Gmbh) discloses a variety of new fused heterocyclic sulphonic amide and ester derivatives with analgesic, antiarrythmic and antipsychotic activities.
Derwent Abstract 22,706 (Pfizer and Co.) discloses quinoline derivatives and their acid addition salts as bronchodilators, but no sulfonamide substituents are disclosed for these compounds.
U.S. Pat. No. 5,240,940 discloses fungicidal compositions comprising a combination of two fungicides, one of which is a quinoline or cinnoline compound. U.S. Pat. No. 4,881,969 discloses sulfonamides as herbicidal agents.
European Published applications 0326330 and 0326328 discloses quinoline, quinazoline and cinnoline fungicides.
JP 63307451 discloses a silver halide color photographic photosensitive material with improved granularity containing a water-soluble coupler capable of a coupling reaction with an oxidant main ingredient in color developing, which coupler may include specific 8-hydroxy-quinoline compounds.
JPO7033729-A discloses the production of N-cyano-N-substituted-arylcarboxyimidamide compounds in which aryl may be 8-quinolyl groups.
International Publication Number WO 96/25399, published Aug. 22, 1996, discloses aroylaniline derivatives which exhibit anti-retroviral activity.
International Publication Number WO 97/03069, published Jan. 30, 1997, discloses substituted heteroaromatic compounds which are protein tyrosine kinase inhibitors, in particular to substituted quinolines and quinazolines.
International Publication Number WO 96/06084, published Feb. 29, 1996, discloses quinolylamine derivatives which are useful for the treatment of arrhythmia.
European Patent Application No. 0206751, published Dec. 30, 1996, discloses 2-substituted-phenylalkenyl-quinoline derivatives which are useful as selective antagonists of leukotrienes of D4.
International Application No. WO 9632015 discloses synergistic fungicidal compositions made of quinoline derivatives and cytochrome complex III inhibitors.
European Patent Application No. 0399818 discloses diarylstyrylquinoline diacids which are leukotriene antagonists and inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.
The present invention particularly provides:
A compound of formula IA
wherein R0 is
a) xe2x80x94(CH2)nxe2x80x94X1,
b) xe2x80x94(CH2)nxe2x80x94C3-C8 cycloalkyl substituted by zero (0) or one (1) R8,
c) xe2x80x94(CH2)pW1X2,
d) xe2x80x94(CH2)pW1CH2X1, or
e) xe2x80x94(CH2)nxe2x80x94CHR9xe2x80x94(CH2)nxe2x80x94X1;
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94CF3, or
f) xe2x80x94NO2;
wherein R2 is
a) xe2x80x94H,
b) xe2x80x94C1-C3alkyl,
c) xe2x80x94OH,
d) xe2x80x94CF3,
e) xe2x80x94CHxe2x95x90CH-furanyl,
f) xe2x80x94CHxe2x95x90CH-phenyl substituted by zero (0) or one (1) R4,
g) xe2x80x94CHxe2x95x90CH-pyridinyl,
h) xe2x80x94(CH2)p-phenyl substituted by zero (0) or one (1) R4,
i) xe2x80x94NHV1,
j) xe2x80x94CH2NHV1, or
k) xe2x80x94CH2Z1;
wherein R3 is
a) xe2x80x94H,
b) xe2x80x94OH,
c) xe2x80x94CF3, or
d) xe2x80x94C1-C3alkyl;
wherein R4 is
a) xe2x80x94H
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94NO2,
f) xe2x80x94CF3,
g) xe2x80x94W1xe2x80x94R10,
h) xe2x80x94C1-C6 alkyl,
i) xe2x80x94C3-C8 cycloalkyl,
j) xe2x80x94[CH2]n-aryl,
k) xe2x80x94[CH2]n-het,
l) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl,
m) xe2x80x94SO2NH-het
n) xe2x80x94CN,
o) xe2x80x94I, or
p) xe2x80x94CH2xe2x80x94OH;
wherein R5 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94W1xe2x80x94R10,
f) xe2x80x94CF3,
g) xe2x80x94C1-C6 alkyl,
h) xe2x80x94C3-C8 cycloalkyl,
i) xe2x80x94(CH2)n-aryl substituted by R6,
j) xe2x80x94(CH2)n-het substituted by R7, or
k) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl;
wherein R6 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein R7 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein R8 is
a) xe2x80x94C1-C4 alkyl,
b) xe2x80x94W1xe2x80x94H, or
c) xe2x80x94CH2W1H;
wherein R9 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94C(O)R11,
d) xe2x80x94C(O)NHR11,
e) xe2x80x94CH(OH)R11,
f) xe2x80x94CH2OH,
g) xe2x80x94CO2R11, or
h) -aryl;
wherein R10 is
a) xe2x80x94H,
b) xe2x80x94C1-C6 alkyl,
c) xe2x80x94C3-C8 cycloalkyl,
d) xe2x80x94(CH2)n-aryl optionally substituted with F, Cl, CH2OH or xe2x80x94NO2,
e) xe2x80x94(CH2)n-het, or
f) xe2x80x94CH2xe2x80x94C3-C3 cycloalkyl;
wherein R1 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94(CH2)nX1, or
d) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl;
wherein X1 is
a) -aryl substituted by zero (0), one (1), two (2), or three (3) R4,
b) -het substituted by zero (0), one (1) or two (2) R5,
c) xe2x80x94C1-C8 alkyl,
d) xe2x80x94CH(OH)-phenyl,
e) xe2x80x94S-phenyl,
f) xe2x80x94NHSO2-phenyl substituted by one (1), two (2) or three (3) R4,
g) xe2x80x94CN,
h) xe2x80x94OH,
i) xe2x80x94C3-C8 cycloalkyl substituted by zero (0), one (1) or two (2) R8, or
j) -4-cyano-2,3,5,6-tetrafluoro-phenyl;
wherein X2 is
a) -aryl substituted by zero (0), one (1), two (2) or three (3) R4,
b) -het substituted by zero (0), one (1) or two (2) R5,
c) xe2x80x94C1-C8 alkyl,
d) xe2x80x94CH(OH)-phenyl, or
e) xe2x80x94C3-C8 cycloalkyl substituted by zero (0), one (1) or two (2) R8;
wherein W1 is
a) xe2x80x94NH,
b) -oxygen, or
c) -sulfur;
wherein V1 is
a) xe2x80x94R11,
b) xe2x80x94C(O)R11,
c) xe2x80x94SO2R11, or
d) xe2x80x94C(O)NHR11;
wherein Z1 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94C(O)R11,
d) xe2x80x94C(O)NHR11, or p1 e) xe2x80x94CO2R11;
wherein -aryl is
a) -phenyl,
b) -naphthyl,
c) -biphenyl,
d) -tetrahydro-naphthyl, or
e) fluorenyl;
wherein -het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocyclic;
wherein -cycloalkyl is a saturated or unsaturated hydrocarbon ring including any bicyclic group in which the above ring is connected to a benzene, heterocyclic or other hydrocarbon ring;
wherein n is zero (0) to six (6), inclusive;
wherein p is one (1), two (2) or three (3);
or a pharmaceutically acceptable salt or N-oxide thereof.
The present invention further provides:
The compound of formula IA provided that:
a) when R0 is xe2x80x94(CH2)nxe2x80x94X1 and X1 is xe2x80x94OH, then n is one or greater; and
b) when R0 is xe2x80x94(CH2)pW1X2, W1 is -oxygen or -sulfur and X2 is phenyl then R4 is other than t-pentyl.
The present invention also provides:
A compound of formula I
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94CF3, or
f) xe2x80x94NO2;
wherein R2 is
a) xe2x80x94H,
b) xe2x80x94C1-C3alkyl,
c) xe2x80x94OH,
d) xe2x80x94CF3,
e) xe2x80x94CHxe2x95x90CH-furanyl,
f) xe2x80x94CHxe2x95x90CH-phenyl substituted by zero (0) or one (1) R4,
g) xe2x80x94CHxe2x95x90CH-pyridinyl, or
h) xe2x80x94(CH2)p-phenyl substituted by zero (0) or one (1) R4;
wherein R3 is
a) xe2x80x94H,
b) xe2x80x94OH,
c) xe2x80x94CF3, or
d) xe2x80x94C1-C3alkyl;
wherein X1 is
a) -phenyl substituted by zero (0) or one (1) R4,
b) -het substituted by zero (0) or one (1) R5,
c) xe2x80x94C1-C12 alkyl,
d) xe2x80x94CH(OH)-phenyl,
e) xe2x80x94S-phenyl,
f) -naphthyl,
g) xe2x80x94NHSO2-phenyl substituted by one (1) R4, or
h) xe2x80x94CN;
wherein het is
a) -1,3,4-thiadiazol-2-yl,
b) -4,5-dihydro-4-oxo-2-thiazolyl,
c) -thiazolyl,
d) -benzothiazolyl,
e) -pyridinyl,
f) -morpholinyl, or
g) -imidazolyl;
wherein R4 is
a) xe2x80x94H
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94NO2,
f) xe2x80x94OCH3,
g) xe2x80x94CF3, or
h) xe2x80x94C1-C4 alkyl;
wherein R5 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94(CH2)nxe2x80x94(phenyl substituted by R6),
f) -thienyl substituted by R7, or
g) xe2x80x94OH;
wherein R6 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein R7 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein n is zero (0) to six (6) inclusive;
or a pharmaceutically acceptable salt or a N-oxide thereof.
The present invention further provides compounds of formula II
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94Cl,
c) xe2x80x94Br, or
d) xe2x80x94NO2;
wherein R2 is
a) xe2x80x94H,
b) xe2x80x94CH3,
c) xe2x80x94CF3,
d) xe2x80x94(CH2)p-phenyl substituted by zero (0) or one (1) R4,
e) xe2x80x94CHxe2x95x90CH-furanyl, or
f) xe2x80x94CHxe2x95x90CH-phenyl substituted by zero (0) or one (1) R4;
wherein X1 is
a) -phenyl substituted by one (1) R4,
b) -het substituted by one (1) R5,
c) xe2x80x94CH(OH)-phenyl,
d) xe2x80x94S-phenyl,
e) -naphthyl,
f) xe2x80x94NHSO2-phenyl substituted by one (1), two (2) or three (3) R4, or
g) xe2x80x94CN;
wherein het is
a) -1,3,4-thiadiazol-2-yl,
b) -4,5-dihydro-4-oxo-2-thiazolyl,
c) -2-thiazolyl, or
d) -2-benzothiazolyl;
wherein R4 is
a) xe2x80x94H,
b) xe2x80x94Cl,
c) xe2x80x94Br,
d) xe2x80x94NO2, or
e) xe2x80x94OCH3;
wherein R5 is
a) xe2x80x94H,
b) xe2x80x94Cl,
c) xe2x80x94(CH2)n-(phenyl substituted by R6),
d) -2-thienyl substituted by R7, or
e) OH;
wherein R6 is
a) xe2x80x94H,
b) xe2x80x94Cl, or
c) xe2x80x94Br;
wherein R7 is
a) xe2x80x94H,
b) xe2x80x94Cl, or
c) xe2x80x94Br,
In another aspect, the present invention provides
A use of a compound of formula IA to prepare a medicament for treating a susceptible cytomegaloviral infection in a mammal
wherein R0 is
a) xe2x80x94(CH2)nxe2x80x94X1,
b) xe2x80x94(CH2)nxe2x80x94C3-C8 cycloalkyl substituted by zero (0) or one (1) R8,
c) xe2x80x94(CH2)pW1X2,
d) xe2x80x94(CH2)pW1CH2X1, or
e) xe2x80x94(CH2)nxe2x80x94CHR9xe2x80x94(CH2)nxe2x80x94X1;
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94CF3, or
f) xe2x80x94NO2;
wherein R2 is
a) xe2x80x94H,
b) xe2x80x94C1-C3alkyl,
c) xe2x80x94OH,
d) xe2x80x94CF3,
e) xe2x80x94CHxe2x95x90CH-furanyl,
f) xe2x80x94CHxe2x95x90CH-phenyl substituted by zero (0) or one (1) R4,
g) xe2x80x94CHxe2x95x90CH-pyridinyl,
h) xe2x80x94(CH2)p-phenyl substituted by zero (0) or one (1) R4,
i) xe2x80x94NHV1,
j) xe2x80x94CH2NHV1, or
k) xe2x80x94CH2Z1;
wherein R3 is
a) xe2x80x94H,
b) xe2x80x94OH,
c) xe2x80x94CF3, or
d) xe2x80x94C1-C3alkyl;
wherein R4 is
a) xe2x80x94H
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94NO2,
f) xe2x80x94CF3,
g) xe2x80x94W1-R10,
h) xe2x80x94C1-C6 alkyl,
i) xe2x80x94C3-C8 cycloalkyl,
j) xe2x80x94[CH2]n-aryl,
k) xe2x80x94[CH2]n-het,
l) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl,
m) xe2x80x94SO2NH-het
n) xe2x80x94CN,
o) xe2x80x94I, or
p) xe2x80x94CH2xe2x80x94OH;
wherein R5 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br,
e) xe2x80x94W1xe2x80x94R10,
f) xe2x80x94CF3,
g) xe2x80x94C1-C6 alkyl,
h) xe2x80x94C3-C8 cycloalkyl,
i) xe2x80x94(CH2)n-aryl substituted by R6,
j) xe2x80x94(CH2)n-het substituted by R7, or
k) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl;
wherein R6 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein R7 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl, or
d) xe2x80x94Br;
wherein R8 is
a) xe2x80x94C1-C4 alkyl,
b) xe2x80x94W1xe2x80x94H, or
c) xe2x80x94CH2W1H;
wherein R9 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94C(O)R11,
d) xe2x80x94C(O)NHR11,
e) xe2x80x94CH(OH)R11,
f) xe2x80x94CH2OH,
g) xe2x80x94CO2R11, or
h) -aryl;
wherein R10 is
a) xe2x80x94H,
b) xe2x80x94C1-C6 alkyl,
c) xe2x80x94C3-C8 cycloalkyl,
d) xe2x80x94(CH2)n-aryl optionally substituted with F, Cl, CH2OH or xe2x80x94NO2,
e) xe2x80x94(CH2)n-het, or
f) xe2x80x94CH2xe2x80x94C3-C3 cycloalkyl;
wherein R11 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94(CH2)nX1, or
d) xe2x80x94CH2xe2x80x94C3-C8 cycloalkyl,
wherein X1 is
a) -aryl substituted by zero (0), one (1), two (2), or three (3) R4,
b) -het substituted by zero (0), one (1) or two (2) R5,
c) xe2x80x94C1-C8 alkyl,
d) xe2x80x94CH(OH)-phenyl,
e) xe2x80x94S-phenyl,
f) xe2x80x94NHSO2-phenyl substituted by one (1), two (2) or three (3) R4,
g) xe2x80x94CN,
h) xe2x80x94OH,
i) xe2x80x94C3-C8 cycloalkyl substituted by zero (0), one (1) or two (2) R1, or
j) -4-cyano-2,3,5,6-tetrafluoro-phenyl;
wherein X2 is
a) -aryl substituted by zero (0), one (1), two (2) or three (3) R4,
b) -het substituted by zero (0), one (1) or two (2) R5,
c) xe2x80x94C1-C8 alkyl,
d) xe2x80x94CH(OH)-phenyl, or
e) xe2x80x94C3-C8 cycloalkyl substituted by zero (0), one (1) or two (2) R8;
wherein W1 is
a) xe2x80x94NH,
b) -oxygen, or
c) -sulfur;
wherein V1 is
a) xe2x80x94R11,
b) xe2x80x94C(O)R11,
c) xe2x80x94SO2R11, or
d) xe2x80x94C(O)NHR11;
wherein Z1 is
a) xe2x80x94C1-C7 alkyl,
b) xe2x80x94C3-C8 cycloalkyl,
c) xe2x80x94C(O)R11,
d) xe2x80x94C(O)NHR11, or
e) xe2x80x94CO2R11;
wherein -aryl is
a) -phenyl,
b) -naphthyl,
c) -biphenyl,
d) -tetrahydro-naphthyl, or
e) fluorenyl;
wherein -het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocyclic;
wherein -cycloalkyl is a saturated or unsaturated hydrocarbon ring including any bicyclic group in which the above ring is connected to a benzene, heterocyclic or other hydrocarbon ring;
wherein n is zero (0) to six (6), inclusive;
wherein p is one (1), two (2) or three (3);
or a pharmaceutically acceptable salt or N-oxide thereof; as well as a method of treating a cytomegalovirus comprising the administration of an effective amount of a compound of the formula IA.
The present invention also provides:
An antiviral pharmaceutical composition which comprises a pharmaceutically acceptable excipient and an effective amount of a compound of formula I.
Further, the present invention provides:
A compound of the formula III
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94C1-C5 alkyl, or
c) xe2x80x94CHxe2x95x90CH-aryl;
wherein R2 is
a) xe2x80x94C1-C10 alkyl,
b) xe2x80x94(CH2)nR3,
c) xe2x80x94CH(R4)R3, or
d) xe2x80x94(CH2)nxe2x80x94X2xe2x80x94R3;
wherein R3 is
a) -aryl,
b) -het substituted by zero (0) to two (2) R5, or
c) xe2x80x94C3-C6 cycloalkyl;
wherein R4 is
a) xe2x80x94C1-C5 alkyl, or
b) -aryl;
wherein X1 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br, or
e) xe2x80x94I;
wherein X2 is
a) xe2x80x94Oxe2x80x94,
b) xe2x80x94Sxe2x80x94, or
c) xe2x80x94NHxe2x80x94;
wherein n is zero (0) to four (4) inclusive;
wherein aryl is
a) phenyl substituted by zero (0) to two (2) R5, or
b) naphthyl substituted by zero (0) to two (2) R1;
wherein het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle; and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen; and if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms; and if chemically feasible, the nitrogen atom may be in the protected form;
wherein R5 is
a) xe2x80x94H,
b) xe2x80x94C1-C5 alkyl,
c) xe2x80x94F,
d) xe2x80x94Cl,
e) xe2x80x94OCH3,
f) xe2x80x94CF3,
g) xe2x80x94NHSO2-het substituted by zero (0) to two (2) xe2x80x94C1-C5 alkyl, or
h) xe2x80x94NHSO2-phenyl;
or a pharmaceutically acceptable salt thereof;
A compound of formula III
wherein R1 is
a) xe2x80x94H,
b) xe2x80x94CH3, or
c) xe2x80x94CHxe2x95x90CH-phenyl;
wherein R2 is
a) xe2x80x94(CH2)nR3,
b) xe2x80x94(CH2)nxe2x80x94X2xe2x80x94R3, or
c) xe2x80x94CH(R4)R3;
wherein R3 is
a) -phenyl substituted by zero (0) to two (2) R5,
b) -het,
c) -naphthyl, or
d) xe2x80x94C3-6 cycloalkyl;
wherein R4 is
a) xe2x80x94CH3, or
b) -phenyl;
wherein R5 is
a) xe2x80x94F,
b) xe2x80x94Cl,
c) xe2x80x94NHSO2-phenyl;
wherre in X1 is
a) xe2x80x94Cl, or
b) xe2x80x94Br;
wherein X2 is
a) xe2x80x94Oxe2x80x94, or
b) xe2x80x94Sxe2x80x94;
wherein het is
a) -imidazolyl, or
b) -indolyl.
The present invention also provides:
A compound of the formula IV
where X1 is
a) xe2x80x94H,
b) xe2x80x94F,
c) xe2x80x94Cl,
d) xe2x80x94Br, or
e) xe2x80x94I;
wherein R2, R3 and R4 may be the same or different and are
a) xe2x80x94C1-C5 alkyl, or
b) -phenyl.
Also provided is:
A compound of formula V
wherein X1 is
a) phenyl substituted by zero (0) to three (3) R4,
b) naphthyl substituted by zero (0) to three (3) R4,
c) fluorenyl substituted by zero (0) to three (3) R4,
d) het substituted by zero (0) to one (1) R5, or
e) 4-cyano-2,3,5,6-tetrafluorophenyl;
wherein R4 is
a) xe2x80x94F,
b) xe2x80x94Cl,
c) xe2x80x94Br,
d) xe2x80x94I,
e) xe2x80x94NO2,
f) xe2x80x94CN,
g) xe2x80x94CF3,
h) xe2x80x94C1-C6 alkyl,
i) phenyl,
j) cyclohexyl,
k) hydroxymethyl,
l) xe2x80x94OR10,
m) xe2x80x94SR10, or
n) xe2x80x94SO2NH-het;
wherein het is
a) 1,3-benzodioxol-4-yl,
b) 1,3-benzodioxo-5-yl,
c) coumarinyl,
d) indazoyl,
e) indolyl,
f) benzothiazolyl,
g) benzothiadiazolyl,
h) quinolinyl,
i) pyridinyl,
j) 1,3,4-thiadiazol-2-yl, or
k) isoxazolyl substituted with one or two C1-C4 alkyl;
wherein R5 is
a) xe2x80x94F,
b) xe2x80x94Cl,
c) xe2x80x94Br,
d) xe2x80x94I,
e) xe2x80x94CF3,
f) xe2x80x94C1-C4-alkyl, or
g) xe2x80x94C1-C2-alkylsubstituted with an
wherein R10 is
a) hydrogen,
b) xe2x80x94C1-C4 alkyl,
c) phenyl,
d) benzyl, or
e) 4-nitrophenyl; as well as
A compound of formula V
wherein het is
a) indazoyl,
b) indoyl, or
c) isoxazolyl substituted with one (1) or two (2) C1-C4 alkyl.
Finally, the present invention provides:
A compound of formula VI or VII
wherein X is
a) xe2x80x94C, or
b) xe2x80x94SO;
wherein Y is
a) xe2x80x94NH,
b) xe2x80x94O, or
c) xe2x80x94S;
wherein EWG is an electron withdrawing group;
wherein R1, R2 and R3 are as defined in claim 1;
wherein R4 is
a) xe2x80x94H,
b) xe2x80x94(CH2)nxe2x80x94CO2xe2x80x94C1-C6 alkyl,
c) xe2x80x94(CH2)m-phenyl optionally substituted with one (1) or two (2) R7,
d) xe2x80x94(CH2)m-het,
e) xe2x80x94C1-C6 alkyl optionally substituted by one R6,
f) xe2x80x94C1-C4 alkyl-NHxe2x80x94COOCH2-benzyl, or
g) xe2x80x94C1-C4 alkyl-Sxe2x80x94CH3;
wherein R5 is pyrrolidin-1-yl optionally substituted with EWG or R6;
wherein n is zero (0) to three (3);
wherein m is zero (0) to one (1);
wherein -het is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocyclic;
wherein R6 is
a) hydroxy,
b) xe2x80x94C1-C6 alkyloxy,
c) mercapto, or
d) xe2x80x94C1-C6 alkylmercapto;
wherein R7 is
a) hydroxy, or
b) xe2x80x94C1-C6 alkyloxy; as well as
A compound of formula VI or VII
wherein R7 is t-butyl;
wherein EWG is
a) xe2x80x94NHxe2x80x94CO2C(CH3)3,
b) xe2x80x94CN,
c) xe2x80x94COX2xe2x80x94C1-C6 alkyl, or
d) xe2x80x94COOH;
wherein X2 is
a) xe2x80x94Oxe2x80x94, or
b) xe2x80x94NH; and
wherein het is
a) 1,3-benzodioxol-4-yl,
b) 1,3-benzodioxol-5-yl, or
c) indolyl.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable.
xe2x80x9cN-oxidexe2x80x9d refers to the oxidized form of the nitrogen in the ring of the 8-hydroxy-quinoline compounds of the present invention. The preparation of such compounds is well known to one of ordinary skill in organic chemistry, including methods such as oxidation with metachloro-peroxy-benzoic acid.
xe2x80x9cElectron-withdrawing groupxe2x80x9d means any substituent on the ring which tends to draw electron density from the ring. Examples of such groups include halogen, nitro, cyano, carboxylic acids, carboxylic esters, sulfoxides, sulfones, sulfonamides, ketones and aldehydes.
xe2x80x9cHalogenxe2x80x9d means fluroine, chlorine, or bromine.
xe2x80x9cHetxe2x80x9d is a 5-, 6- or 7-membered saturated or unsaturated ring containing from one (1) to three (3) heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle; and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen; and if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms; and if chemically feasible, the nitrogen atom may be in the protected form; and substituted or unsubstituted. Examples of xe2x80x9chetxe2x80x9d include the following: thiadiazolyl, thiazolyl, benzothiazolyl, pyridinyl (or pyridyl), morpholinyl, imidazolyl, indolyl, and piperazinyl.
The compounds of the present invention are named according to the IUPAC or CAS nomenclature system.
The carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Ci-Cj indicates a moiety of the integer xe2x80x9cixe2x80x9d to the integer xe2x80x9cjxe2x80x9d carbon atoms, inclusive. Thus, for example, (C1-C3)alkyl refers to alkyl of one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, straight and branched forms thereof.
Throughout this application, abbreviations which are well known to one of ordinary skill in the art may be used, such as xe2x80x9cPhxe2x80x9d for phenyl, xe2x80x9cMexe2x80x9d for methyl, and xe2x80x9cEtxe2x80x9d for ethyl.
The following Charts A-I describe the preparation of the compounds of the present invention. All of the starting materials are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the final compounds of the present invention are prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in the charts are as defined below or as in the claims.
The preparation of the starting materials, 8-hydroxyquinoline-7-carboxylic acids, is accomplished in low to moderate yields by the carboxylation of 8-hydroxy-quinolines, which are either commercially available or which are prepared by literature methods: G. S. Bajwa, K. E. Hartman, and M. N. Jouillie, Journal of Medicinal Chemistry, Vol.16, No. 2, pages 134-138 (1973); L. C. March, W. A. Romanchick, G. S. Bajwa, and M. M. Jouillie, Journal of Medicinal Chemistry, Vol. 16, No. 4, pages 337-342 (1973). The compound of formula A-1 is reacted with K2CO3 (3 eq.), CO2(800 p.s.i) at 170xc2x0 for 7 days, to yield the compound of formula A-2. J. Hannah et al., Journal of Medicinal Chemistry, Vol. 21, No. 11, pages 1093-1100 (1978). (R1 and R2 in formula A-1 are the same as R1 and R2 in formula A-2.) The compound of formula A-2 wherein R1 is xe2x80x94H and R2 is xe2x80x94H is the intermediate compound of Preparation 1 below. The compound of formula A-2 wherein R1 is xe2x80x94F and R2 is xe2x80x94H is the intermediate compound of Preparation 4 below. The compound of formula A-2 wherein R1 is xe2x80x94Cl and R2 is xe2x80x94H is the intermediate compound of Preparation 3 below. The compound of formula A-2 wherein R1 is xe2x80x94H and R2 is xe2x80x94CH3 is the intermediate compound of Preparation 5 below. 
Bromination of 8-hydroxyquinoline-7-carboxylic acid of formula B-1 with one equivalent of bromine (HOAc, reflux, 1 hr) yields 5-bromo-8-hydroxy-7-quinoline-carboxylic acid of formula B-2 in quantitative yield, which is prepared in Preparation 2 below. R. Schmitt and F. Engelmann, Chem. Ber., 20; 1887; 2694. 
The acid of formula C-1, prepared as described in Charts A and B above, is condensed with the amine of formula C-2, which is commercially available (e.g, p-chloro or p-nitrobenzylamine), under appropriate conditions (EDC is used as the coupling agent, HOBt, DMF, rt, 18 hr) to yield the compound of formula C-3. (R1 and R2 in formula C-1 are the same as R1 and R2 in formula C-3. X in formula C-2 is the same as X in formula C-3.) The compound of formula C-3 wherein R1 is xe2x80x94Br, R2 is xe2x80x94H and X is xe2x80x94Cl is the final compound of Example 9 below. The compound of formula C-3 wherein R1 is xe2x80x94H, R2 is xe2x80x94CH3 and X is xe2x80x94Cl is the final compound of Example 10 below. The compound of formula C-3 wherein R1 is xe2x80x94Cl, R2 is xe2x80x94H and X is xe2x80x94Cl is the final compound of Example 11 below. The compound of formula C-3 wherein R1 is xe2x80x94H, R2 is xe2x80x94H and X is xe2x80x94NO2 is the final compound of Example 12 below. The compound of formula C-3 wherein R1 is xe2x80x94F, R2 is xe2x80x94H and X is xe2x80x94Cl is the final compound of Example 16 below. Chart C is the preferred coupling method for benzylamines. 
Under the same conditions as in Chart C above (i.e., EDC, HOBT, DMF, rt, 7 days), the acid of formula D-1 is condensed with the heterocyclic amine of formula D-2 to give the final compound of formula D-3, which is prepared in Example 8 below. 
Chart E discloses a more efficient method of coupling the 8-hydroxyquinoline-7-carboxylic acids with anilines and heterocyclic amines utilizing PCl3 as the condensing agent. H. Singh, A. K. Singh, S. Sharma, R. N. Iyer, J. Med. Chem., 20:826 (1977); H. Singh, S. Sharma, R. N. Iyer, Ind. J. Chem., 15B:73 (1977); S. K. Dubey, A. K. Singh, H. Singh, S. Sharma, R. N. Iyer, J. Med. Chem., 37:999 (1994). The compound of formula E-1 is coupled with the compound of formula E-2 (using PC3, xylenes, at reflux, for 18 hr) to yield the compound of formula E-3 wherein X is xe2x80x94H (which is the final compound of Example 5 below) or X is xe2x80x94Br (which is the final compound of Example 6 below). (X in formula E-1 is the same as X in formula E-3.) Chart E is the preferred coupling method for heterocyclic amines. 
The required thiazolones of formula F-3 are prepared in three steps from commercially available acids of formula F-1 as follows: the compound of formula F-1 is first treated with P(red) in Br and is then treated with AcCl in methanol to yield the compound of formula F-2. This compound is then reacted with thiourea at ethanol at reflux to yield the compound of formula F-3. T. Sohda et al., Chem. Pharm. Bull., Vol. 30, No. 10, pages 3601-3616 (1982). 
Anilines are also coupled in low to moderate yields under the conditions of Chart E. Thus, the compound of formula G-1 is coupled with the compound of formula G-2 (using PCl3, xylenes, at reflux, for 18 hours) to yield the compound of formula G-3. (R1 in formula G-1 is the same as R1 in formula G-3.) The compound of formula G-3 wherein R1 is xe2x80x94H is the final compound of Example 3 below; the compound of formula G-3 wherein R1 is xe2x80x94Br is the final compound of Example 4 below; and the compound of formula G-3 wherein R1 is xe2x80x94Cl is the final compound of Example 15 below. The coupling conditions of this reaction are preferred when anilines are used. 
Chart H discloses another method of coupling which is used in the condensation of benzylamines, although the yields are lower than found for the EDC couplings. The compound of formula H-1 is coupled with the compound of formula H-2 (using PCl3, xylenes, at reflux for 18 hr) to yield the compound of formula H-3, which is the final compound of Example 1 below. 
Other heterocyclic amines are also condensed with quinoline carboxylic acids under these conditions. The quinoline carboxylic acid of formula I-1 (which was prepared in Chart A above) is coupled with the appropriate heterocyclic amine of formula I-2, I-4, I-6 or I-8 (using PCl3, xylenes, at reflux, for 18 hours) to yield the compound of formula I-3, I-5, I-7 or I-9, respectively. The compound of formula I-3 is the final compound of Example 2 below; the compound of formula I-5 is the final compound of Example 7 below; the compound of formula I-7 is the compound of Example 13 below which is useful as an intermediate; and the compound of formula I-9 is the final compound of Example 14 below. 
The preparation of the starting materials is accomplished by O-methylation of commercially-avaiable 5,7-dihalo-8-hydroxyquinolines according to the procedure of R. A. W. Johnstone and M. E. Rose in Tetrahedron, vol. 35, page 21169 (1979). The compound of formula J-1 is treated with t-butyllithium or n-butyllithium at low temperature in ether/toluene, then exposed to sulfur dioxide gas to prepare the compound of formula J-2. Conversion of the compound of formula J-2 to the sulfonyl chloride of formula J-3 is accomplished by treatment with N-chlorosuccinimide (CH2Cl2, 3 hr). The sulfonamide of formula J-4 is then prepared by reaction of the sulfonyl chloride of formula J-3 with 1 equivalent of a primary amine of the formula R2NH2 and 2 equivalents of pyridine in CH2Cl2 (15 hr). Finally, the compound of formula J-5 is prepared using either excess pyridinium hydrochloride (220xc2x0 C., 10 min) or excess boron tribromide (CH2Cl2, 1.5 hr). 
Compounds of the structure K-3 are prepared from commercially-available 5,7-dihalo-8-hydroxyquinolines (K-1) in two steps. Formation of the silylether intermediates K-2 is accomplished by reaction of the 8-hydroxyquinolines K-1 with chlorotrialkylsilanes in the presence of imidazole and DMF at room temperature for 18-20 hours. The intermediates are then treated with t-butyllithium or n-butyllithium at low temperature in THF to give the compound of formula K-3. 
To a mixture of o-anidisine of L-1 and ethyl-4,4,4-trifluoroacetoacetate of L-2 is added 6N HCl. The resulting enamine is heated in diphenylether at 250xc2x0 C. to produce 4-hydroxy-8-methoxy-2-trifluoromethylquioline of L-3. 
The compound of M-1 is chlorinated with phosphorus oxychloride in CH2Cl2/DMF at room temperature. The resulting chloride of M-2 is reductively cleaved by hydrogenation in EtOH, Et3N to give M-3. Methyl ether deprotection with pyridine hydrochloride at 220xc2x0 C. gives 2-trifluoromethyl-8-hydroxyquinoline of M-4. This material is carboxylated to M-5 under Kolbe-Schmidt conditions. Standard amide couplings gives the desired products of M-6. 
Alternatively, pyridine hydrochloride deprotection of N-1 gives the 4,8-dihydroxy-quinoline of N-2, which again is carboxylated under Kolbe-Schmidt conditions to give N-3. Standard amide couplings give the desired products of N-4. 
Aryl aldehydes of O-2 are condensed with 8-hydroxyquinaldine of O-1 at 180xc2x0 C. to form the 2-styryt-8-hydroxyquinolines of O-3. These are carboxylated under Kolbe-Schmidt conditions to give O-4. Standard couplings of the resulting acid with amines gives the desired amides O-5. 
The preparation of the starting material of formula P-1 is accomplished by chlorination of commercially-available 8-hydroxyquinaldine according to the procedure described in DE 1770065. The compound of formula P-1 is then treated with neat flourosulfonic acid at 120xc2x0 C. to form the compound of formula P-2. Finally, the sulfonamides of formula P-3 are prepared by heating to 140xc2x0 C. a mixture of 1 eq of the sulfonyl flouride of formula P-2, 2 eq of the primary amine of formula RNH2 and 3 eq of N,N-diisopropylethylamine in chlorobenzene. 
The preparation of the starting material of formula Q-1 is accomplished by O-methylation of commercially-available 5,7-dibromo-2-methyl-8-quinolinol according to the procedure of R. A. W. Johnstone and M. E. Rose in Tetrahedron, vol. 35, page 21169 (1979). The styrene derivative of formula Q-2 is obtained by heating the 2-methylquinoline of formula Q-1 with benzaldehyde for 18 h. The intermediate of formula Q-2 (which corresponds to J-1, R1=CHxe2x95x90CHPh, X1=X2=Br) is then advanced in four steps to the sulfonamides of formula Q-3 (which corresponds to J-5, R1=CHxe2x95x90CHPh, X1=Cl; R2=R) following the route previously described in Chart J. 
The preparation of the starting material of formula R-1 is accomplished by chlorination of commercially-available 8-hydroxyquinaldine according to the procedure described in DE 1770065. The 7-iodo derivative of formula R-2 is then prepared by reaction of the quinoline of formula R-1 with iodine monochloride in methanol. The compound of formula R-2 is treated successively with methyl magnesium bromide and n-butyllithium at xe2x88x9278xc2x0 C. in THF, then exposed to sulfur dioxide gas to prepare the compound of formula R-3. Conversion of the compound of formula R-3 to the sulfonyl chloride of formula R-4 is accomplished by treatment with N-chlorosuccinimide in methylene chloride at room temperature for 2 h. The sulfonamide of formula R-5 is then prepared by reaction of the sulfonyl chloride of formula R-4 with 2-(4-aminophenyl)ethylamine and pyridine in methylene chloride. Finally, the compound of formula R-6 is prepared by reaction of the compound of formula R-5 with excess sulfonyl chloride of the formula RSO2Cl in pyridine. 
The commercially-available 5-flouro-8-hydroxyquinoline of formula S-1 is treated with neat chlorosulfonic acid at 90-105xc2x0 C. to form the sulfonyl chloride of formula S-2. The sulfonamide of formula S-3 is then prepared by reaction of 1 eq of the sulfonyl chloride of formula S-2 with 3 eq of benzylamine in THF. 
Commercially available 8-hydroxyquinoline (T-1) is converted to the 7-carboxylic acid (T-2) by heating at 175xc2x0 C. in the presence of potassium carbonate under 800 psi carbon dioxide gas for 7 days. The acid is then condensed with various aliphatic amines after activation with either 1,1xe2x80x2-carbonyldiimidazole, or alternatively 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole to afford the desired amides of the formula T-3. The above amides are prepared either as discrete analogues or as part of a parallel synthesis block. 
Anhydride U-1 is prepared from 8-hydroxy-7-quinoline carboxylic acid using 2,2,2-trichloroethyl chloroformate and diisopropylethylamine. The purity of the starting materials is crucial for this reaction to succeed; particularly, any trace of any metalic cations but alkali cations, or Lewis acids, has to be avoided, as they lead to an inhibition of the reaction as well as to decarboxylation of anhydride U-1, probably through a chelation of both starting material and product; during the whole course of the reaction, strictly basic conditions have to be maintained, acidic conditions favoring a decarboxylation of the product as well. Ester U-3 is prepared from 8-hydroxy-7-quinoline carboxylic acid as well, the 8-hydroxy substituent being first protected to ester U-2 according to a literature procedure (German Patent No. 540842, Dec. 10, 1931) and subsequent activation of the 7-carboxylic acid as its fluoride, using cyanuric fluoride and diisopropylethylamine. 
N-Aryl-8-hydroxy-7-quinolinecarboxamides V-4-14 are prepared as single compounds from anhydride U-1 (Chart U) following GP II described below. Both amide coupling and deprotection of the 8-hydroxy substituent can be realized in a single step with primary amines, provided some traces of water are present in the reaction mixture. (No water needs to be added; water coming from glassware and used solvents is enough to ensure a complete deprotectino, at least on small scale.) Probably, the amide function of the still protected intermediate is nucleophilic enough to attack the carbonate at the 7-position via a six-membered ring; subsequent hydrolysis, catalyzed by pyridinium chloride, leads to the desired amides. Similarly, N-Aryl-8-hydroxy-7-quinolinecarboxamides V-21-36 are prepared by parallel synthesis from anhydride U-1, following GP III described below. N-Aryl-8-hydroxy-7-quinolinecarboxamides V-15-20 are prepared as single compounds following GP IV described below from ester U-3 (Chart U). After the coupling step is achieved (6 h to 5 days depending on the amine), methanol is added, which leads to the deprotection of the 8-hydroxy substituent within 6 to 24 h. N-aryl-8-hydroxyquinoline-7-carboxamides V-17-20 as well as V-37-94 are also prepared by parallel synthesis from ester U-3, following GP V described below.
When parallel synthesis is used, some impurities appear occasionally besides the desired product, mainly the carbamate resulting from an attack of the amine at the carbonate positions when anhydride U-1 is involved, or methyl 8-hydroxy-7-quinoline carboxylate after methanolic treatment of the reaction mixture from ester U-3. 
The synthesis of 2-amino-5-alkyl-1,3,4-thiadiazoles W-95-98, W-100-102, W-105, W-108 and X-109-117, which are to be coupled with the activated 8-hydroxy-7-quinoline carboxylic acid derivatives U-1 or U-3 (refer to Chart U) to afford the corresponding 8-hydroxy-N-(1,3,4-thiadiazol-2-yl)-7-quinolinecarboxamides X-118-136, required one to four steps. 2-Amino-5-bromo-1,3,4-thiadiazole W-95 is prepared through bromination of commercially available 2-amino-1,3,4-thiadiazole. Thiadiazole derivatives W-96-98 are prepared through direct bromide displacement of thiadiazole W-95 with the corresponding amines. Using the same strategy, nitrile W-100 is prepared from aminonitrile W-99, itself prepared from piperonal through a Strecker synthesis. Displacement of the bromide of thiadiazole W-95 with L- and D-phenylalanine methyl esters leads to esters W-101 and W-102, though in low yields. Known literature procedures are used to prepare amino acids W-103 and W-106, of which acid groups are converted into the corresponding tert-butyl esters (compounds W-104 and W-107) by standard procedures; subsequent bromide displacement as last step affords esters W-105 and W-108. 
Bromide displacement with commercially available piperonyl amine leads to thiadiazole W-109; similarly, using some amino acid tert-butyl esters leads to esters X-110 to X-117. 
These thiadiazoles, as well as commercially available 2-amino-5-(trifluoromethyl)-1,3,4-thiadiazole, are then coupled using the same methodology as described for the amides V-4-20 from anhydride U-1 or ester U-3 to give amides Y-118-125 or xcex3-126-136, respectively. Depending on the applied work-up procedure, these compounds are isolated as the free compounds, as the hydrochloride salt or as a hydrate. 
The tert-butyl esters are hydrolyzed in selected examples to yield acids Z-137-139. These acids are isolated as their corresponding hydrotrifluoroacetates. 
N-(5-alkylamino-1,3,4-thiadiazol-2-yl)-8-hydroxy-7-quinolinesul fonamides are prepared from the corresponding thiadiazoles and 8-hydroxy-7-quinolinesulfonyl chloride AA-C, prepared in two steps from a 8-hydroxy-7-halogenoquinoline AA-A. 
It will be apparent to those skilled in the art that the described synthetic procedures are merely representative in nature and that alternative synthetic processes are known to one of ordinary skill in organic chemistry.
The compounds of the present invention and pharmaceutically acceptable salts thereof are useful as antiviral agents. Thus, these compounds are useful to combat viral infections in animals, including man. Specifically, these compounds have anti-viral activity against the herpes virus, cytomegalovirus (CMV). Many of these compounds are also active against other herpes viruses, such as the varicella zoster virus, the Epstein-Barr virus, the herpes simplex virus, and the human herpes virus type 8 (HHV-8).
Also, while many of the compounds of the present invention have shown activity against the CMV polymerase, these compounds may be active against the cytomegalovirus by this or other mechanisms of action. Thus, the description below of these compounds"" activity against the CMV polymerase is not meant to limit the present invention to a:specific mechanism of action.
The compounds of the present invention have shown activity in one or more of the assays described below. All of these assays are indicative of a compound""s activity and thus of its use as an anti-viral agent.
The HCMV polymerase assay is performed using a scintillation proximity assay (SPA) as described in several references, such as N. D. Cook, et al., Pharmaceutical Manufacturing International, pages 49-53 (1992); K. Takeuchi, Laboratory Practice, September issue (1992); U.S. Pat. No. 4,568,649 (1986); which are incorporated by reference herein. Reactions are performed in 96-well plates. The assay is conducted in 100 xcexcl volume with 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl2, 0.36 mg/ml BSA, and 90 nM 3H-dTTP. Assays are run with and without CHAPS, (3-[(3-Cholamidopropyl)-dimethylammonio]-1-propane-sulfonate) at a final concentration of 2 mM. HCMV is diluted in enzyme dilution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100 pg/ml BSA, and 0.01% sodium azide. The HCMV polymerase, which is expressed in recombinant baculovirus-infected SF-9 cells and purified according to literature procedures, is added at 10% (or 10 xcexcl) of the final reaction volume, i.e., 100 xcexcl. Compounds are diluted in 50% DMSO and 10 xcexcl are added to each well. Control wells contain an equivalent concentration of DMSO. Unless noted otherwise, reactions are initiated via the addition of 6 nM biotinylated poly(dA)-oligo(dT) template/primer to reaction mixtures containing the enzyme, substrate, and compounds of interest. Plates are incubated in a 25xc2x0 C. of 37xc2x0 C. H2O bath and terminated via the addition of 40 xcexcl/reaction of 0.5 M EDTA (pH 8) per well. Reactions are terminated within the time-frame during which substrate incorporation is linear and varied depending upon the enzyme and conditions used, i.e., 30 min. for HCMV polymerase. Ten xcexcl of streptavidin-SPA beads (20 mg/ml in PBS/10% glycerol) are added following termination of the reaction. Plates are incubated 10 min. at 37xc2x0 C., then equilibrated to room temperature, and counted on a Packard Topcount. Linear regressions are performed and IC50""s are calculated using computer software. Results of the testing of compounds of the present invention in this assay are shown in Tables 1, 2, 5, 9, 10, 11, 13 (except for the last compound which was tested under modified conditions) and 14 below.
A modified version of the above HCMV polymerase assay is performed as described above, but with the following changes: Compounds are diluted in 100% DMSO until final dilution into assay buffer. In the previous assay, compounds are diluted in 50% DMSO. 4.5 mM dithiotherotol (DTT) is added to the polymerase buffer. Also, a different lot of CMV polymerase is used, which appears to be more active resulting in a more rapid polymerase reaction. Results of the testing of compounds of the present invention in this assay are shown in Tables 3, 6 and 7 below.
Compounds are tested for direct antiviral activity against HCMV using a cell culture based assay. An ELISA (enzyme linked immunosorbant assay) format is used as described in W. A. Tatarowicz, N. S. Lurain and K. D. Thompson, J. Virol. Meth., 35:207-215 (1991). Human foreskin fibroblast cells are infected with HCMV at a multiplicity of 0.025 plaque forming units per microtiter plate well for a period of 90 minutes. The virus inocula is removed and a suspension of test compound prepared in tissue culture media is added for a period of 4 days. The growth media is aspirated and replaced with 95% ethanol to allow fixation of virus infected cultures. The ethanol is removed and the wells are washed twice with saline. A solution of 2% dry fat milk, 1% bovine sera albumin prepared in saline is added to wells to allow for non-specific binding of protein material to plastic surfaces for 1 hr. Murine monoclonal antibody prepared in saline directed against the late (65 KD) matrix protein of HCMV is added to test wells for 1 hr. The wells are washed twice and antibody, conjugated with the enzyme horse radish peroxidase, with specificity against murine IgG is added to test wells for 1 hr. Test wells are washed three times with saline. A solution of o-phenylene diamine, a substrate for horse radish peroxidase is added for 15 minutes at which time enzymatic conversion occurs indicating reactivity of the enzyme with its substrate. This conversion is evident as a color reaction which was spectrophoretically monitored at 490 nm. The intensity of the color indirectly reflects the presence of antibody directed against the viral 65 KD matrix antigen. The presence of the viral matrix antigen refects the amount of HCMV replication. Thus, test wells, in which little viral replication has occurred, would have little or no antibody binding and are present with low levels of color. Non-infected wells serve as the assay background control. Results of the testing of compounds of the present invention in this assay are shown in Tables 4, 7 and 12 below.
These compounds of the present invention are administered in a pharmaceutical composition containing the compound in combination with a suitable excipient, the composition being useful in combating viral infections. Pharmaceutical compositions containing a compound appropriate for antiviral use are prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington""s Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co., 15th Ed., 1975), which is hereby incorporated by reference herein.
The compounds of the present invention are administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, orally, or rectally, depending on whether the preparation is used to treat internal or external viral infections.
For internal infections, the compositions are administered orally or parenterally at dose levels, calculated as the free base, of about 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and are used in man in a unit dosage form, administered one to four times daily in the amount of 1 to 1000 mg per unit dose.
For parenteral administration or for administration as drops, as for eye infections, the compounds are presented in aqueous solution in a concentration of from about 0.1 to 10%, more preferably about 0.1 to 7%. The solution may contain other ingredients, such as emulsifiers, antioxidants or buffers.
The exact regimen for administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment and, of course, the judgment of the attending practitioner.
The following compounds of the present invention are preferred:
N-[5-[(4-Chlorophenyl)methyl]-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;
5-Bromo-N-(4-chlorophenyl)-8-hydroxy-7-quinolinecarboxamide;
5-Chloro-N-(4-chlorophenyl)-8-hydroxy-7-quinolinecarboxamide;
N-[(4-Chlorophenyl)methyl]-8-hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide;
8-Hydroxy-N-(2-hydroxy-2-phenylethyl)-2-(2-phenylethenyl)-7-quinolinecarboxamide;
N-[(4-Chlorophenyl)methyl]-8-hydroxy-2-(2-phenylethenyl)-7-quinolinecarboxamide;
8-Hydroxy-2-(2-phenylethenyl)-N-[2-(phenylthio)ethyl]-7-quinolinecarboxamide;
8-Hydroxy-N-(2-hydroxy-2-phenylethyl )-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide;
N-[(4-Chlorophenyl)methyl]-2-[2-(2-furyl)ethenyl]-8-hydroxy-7-quinolinecarboxamide;
5-chloro-8-hydroxy-2-methyl-N-(3-phenylpropyl)-7-quinolinecarboxamide;
5-chloro-8-hydroxy-2-methyl-N-[(2-phenylthio)ethyl]-7-quinolinecarboxamide;
8-hydroxy-N-[5-[4-[(1-methylethyl)phenylsulfonyl]amino]pentyl]-7-quinolinecarboxamide;
8-hydroxy-N-(cyanomethyl)-7-quinolinecarboxamide;
8-hydroxy-N-(2-hydroxy-2-phenylethyl)-2-[2-(4-methoxyphenyl)ethyl]-7-quinolinecarboxamide;
N-(2,2-Diphenylethyl)-8-hydroxy-7-quinolinecarboxamide;
N-(3,3-Diphenylpropyl)-8-hydroxy-7-quinolinecarboxamide;
8-Hydroxy-N-(cis-myrtanyl)-7-quinolinecarboxamide;
8-Hydroxy-N-(diphenylmethyl)-7-quinolinecarboxamide;
8-Hydroxy-N-(2-octyl)-7-quinolinecarboxamide;
N-[2-((1R,2S)-1,2-Diphenyl-1-hydroxy)ethyl]-8-hydroxy-7-quinolinecarboxamide;
8-Hydroxy-N-nonyl-7-quinolinecarboxamide;
N-(4-tert-Butylcyclohexyl)-8-hydroxy-7-quinolinecarboxamide;
R-8-Hydroxy-N-[1-(1-naphthyl)ethyl]-7-quinolinecarboxamide;
S-N-[1-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;
N-[2-((1S,2R)-1,2-Diphenyl-1-hydroxy)ethyl]-8-hydroxy-7-quinolinecarboxamide;
S-8-Hydroxy-N-[1-(1-naphthyl)ethyl]-7-quinolinecarboxarnide;
N-[(2-Chloro-6-phenoxy-phenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;
S-8-Hydroxy-N-[2-(1-hydroxy-3-[4-hydroxyphenyl])propyl]-7-quinolinecarboxamide;
8-Hydroxy-N-undecyl-7-quinolinecarboxamide;
8-Hydroxy-N-(2-methylcyclohexyl)-7-quinolinecarboxamide;
N-[1-(2-Ethyl)hexyl]-8-hydroxy-7-quinolinecarboxamide;
8-Hydroxy-N-(1-naphthalenylmethyl)-7-quinolinecarboxamide;
8-Hydroxy-N-[2-(2-[4-phenoxy]phenyl)ethyl]-7-quinolinecarboxamide;
R-N-[1-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;
S-O-Benzyl-N-[7-(7-Carboxy-8-hydroxy)quinolyl]-tyrosine, methyl ester;
N-[2-(4-Bromophenyl)ethyl]-8-hydroxy-7-quinolinecarboxamide;
N-(4-Cyanophenyl)-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
N-(3-Chlorophenyl)-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
N-Fluoren-2-yl-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
8-Hydroxy-N-{4-[(indazo-6-ylamino)sulfonyl]phenyl}-7-quinolinecarboxamide monohydrochloride;
N-(3-Benzoxyphenyl )-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
N-(4-Benzoxyphenyl)-8-hydroxy-7-quinol inecarboxamide monohydrochloride;
8-Hydroxy-N-[4-(4-nitrophenoxy)phenyl]-7-quinolinecarboxamide monohydrochloride;
8-Hydroxy-N-naphth-1-yl-7-quinolinecarboxamide;
N-(2-Chloro-4-nitrophenyl)-8-hydroxy-7-quinolinecarboxamide;
N-Biphen-2-yl-8-hydroxy-7-quinolinecarboxamide;
N-(4-Chloro-2-methylphenyl)-8-hydroxy-7-quinolinecarboxamide;
8-Hydroxy-N-(4-propylphenyl)-7-quinolinecarboxamide;
8-Hydroxy-N-[4-(hydroxymethyl)phenyl]-7-quinolinecarboxamide;
8-Hydroxy-N-indazol-5-yl-7-quinolinecarboxamide;
8-Hydroxy-N-(5-iodo-2-methylphenyl)-7-quinolinecarboxamide;
8-Hydroxy-N-[5-(2-phenylethyl)amino-1,3,4-thiadiazol-2-yl]-7-quinolinecarboxamide monohydrochloride;
N-[5-(Butylamino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
5-Bromo-N-[(4-chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;
5-Chloro-N-[(4-chlorophenyl)methyl]-8-hydroxy-7-quinolinecarboxamide;
N-Heptyl-8-hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-7-quinolinecarboxamide;
N-Heptyl-8-hydroxy-2-(2-phenylethenyl)-7-quinolinecarboxamide;
8-Hydroxy-2-[2-(4-methoxyphenyl)ethenyl]-N-[2-(phenylthio)ethyl]-7-quinolinecarboxamide;
5-Chloro-N-[(4-chlorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinecarboxamide;
N-[(4-Chlorophenyl)methyl]-8-hydroxy-5-nitro-7-quinolinecarboxamide;
N-[5-[3-(4-Chlorophenyl)methyl]-4,5-dihydro-4-oxo-2-thiazolyl]-8-hydroxy-7-quinolinecarboxamide;
(E)-8-Hydroxy-2-(2-phenylethenyl)-N-(3-phenylpropyl)-7-quinolinecarboxamide;
N-{5-[(1,3-Benzodioxol-5-ylcyanomethyl)amino]-1,3,4-thiadiazol-2-yl}-8-hydroxy-7-quinolinecarboxamide monohydrochloride;
N-[5-({1,3-Benzodioxol-5-yl-[(tert-butoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide semihydrate;
N-[5-({1,3-Benzodioxol-4-yl-[(tert-butoxy)carbonyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide semihydrate;
(S)-N-[5-({[(tert-Butoxy)carbonyl]-[4-hydroxybenzyl]methyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;
(S)-N-[5-({5-[Benzoxy]amido-1-[(tert-butoxy)carbonyl]pentyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide;
(S)-N-[5-({1-[(tert-Butoxy)carbonyl]-2-indol-3-ylethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide monohydrate; and
(S)-N-[5-({1-[(tert-Butoxy)carbonyl]-2-[4-(tert-butoxy)phenyl]ethyl}amino)-1,3,4-thiadiazol-2-yl]-8-hydroxy-7-quinolinecarboxamide monohydrate.
The following sulfonamide compounds of the present invention are preferred:
5-Chloro-8-hydroxy-2-methyl-N-[2-(phenylthio)ethyl]-7-quinolinesulfonamide;
5-Chloro-N-(4-chlorophenyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide;
5-Chloro-N-[4-fluorophenyl)methyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide;
5-Chloro-8-hydroxy-2-methyl-N-(1-naphthalenylmethyl)-7-quinolinesulfonamide;
5-Chloro-N-(cyclohexylmethyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide;
5-Chloro-8-hydroxy-2-methyl-N-(3-phenylpropyl)-7-quinolinesulfonamide;
5-Chloro-8-hydroxy-2-methyl-N-(2-phenoxyethyl )-7-quinolinesulfonamide;
5-Chloro-N-(diphenylmethyl)-8-hydroxy-2-methyl-7-quinolinesulfonamide;
(R)-5-Chloro-8-hydroxy-2-methyl-N-(1-phenylethyl)-7-quinolinesulfonamide;
(S)-5-Chloro-8-hydroxy-2-methyl-N-(1-phenylethyl)-7-quinolinesulfonamide;
5-Chloro-N-[2-(4-chlorophenyl)ethyl]-8-hydroxy-7-quinolinesulfonamide;
5-Bromo-8-hydroxy-N-(phenylmethyl)-7-quinolinesulfonamide;
5-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]-8-hydroxy-2-methyl-7-quinolinesulfonamide;
(E)-5-Chloro-8-hydroxy-2-(2-phenylethenyl)-N-[2-(phenylthio)ethyl]-7-quinolinesulfonamide; and
5-Chloro-8-hydroxy-2-methyl-N-[2-[4-[(phenylsulfonyl)amino]phenyl]ethyl]-7-quinolinesulfonamide.

8-Hydroxyquinoline (50.0 g) and potassium carbonate (142.8 g) are mixed together in a stainless steel bomb and heated at 170xc2x0 C. under 1200 p.s.i. CO2 for 7 days. The reaction is then cooled and the resulting solid is partitioned between water (6 L) and EtOAc (1 L). The organic layer is extracted with water (2xc3x97300 mL). The combined aqueous layers are extracted with EtOAc (3xc3x97500 mL). The aqueous layer is then acidified to pH 4.5 with conc. HCl. The resulting solid is collected, dried and triturated with i-PrOH to yield 51.97 g of the title compound as a tan solid.
Physical characteristics are as follows:
1H NMR (300 MHz, DMSO) xcex4 8.89, 8.58, 7.89, 7.78, 7.28.